Frederick Cassidy

Aminophosphonic acid containing inhibitors of human collagenase: modification of the P1 residue

Abstract A series of peptidomimetic aminophosphonic acid derivatives was synthesized and evaluated in vitro for inhibition of human fibroblast collagenase activity. Incorporation of a bromonaphthalimidoethyl moiety at the P1 position led to potent inhibitors, such as 14a (IC50 0.02 μM).

Design and synthesis of novel muscarinic agonists containing the 1,2,4-triazine ring as an ester bioisostere

Abstract Replacement of the ester group in methyl quinuclidine-3-car☐ylate1 with a 1,2,4-triazine ring afforded the high affinity muscarinic partial agonist6a. Analogues7a,7b and7d which incorporate the 1-azabicyclo[2.2.1]heptane ring also display high affinity for muscarinic receptors.

Design and synthesis of azabicyclic muscarinic agonists incorporating an oxime ether functionality

Abstract Replacement of the ester group of methyl quinuclidine-3-carboxylate 2 with an oxime ether afforded a series of potent muscarinic agonists with efficacies ranging from full to partial agonism. From an investigation of the relationship between central selectivity and efficacy, the propargyl ether 5g emerged as a high affinity partial agonist with a good separation between central and peripheral actions.

Unexpected products from the reactions of 6-cyano-, and 6-nitro-3.4-epoxy 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran with azacyclotridecanone

Abstract The title reactions furnished the pyran ring cleaved product (3) and the tetracyclic chromene (5), rather than the expected 4-cyclicamido-3-hydroxy benzopyrans (1,RCN and NO 2 , respectively, n=11). Mechanisms proposed for these reactions require a strong electron withdrawing group at C(6) in the benzopyran, and a conformationally mobile lactam ring.

The synthesis of 8,10,12-triazaprostaglandin analogues: 1,2,4-triazolidine-3,5-dione derivatives

In the search for active, more selective prostaglandin analogues, the synthesis of 8,10,12-tri-azaprostaglandin analogues has been achieved from readily available 4-methyl-1,2,4-triazolidine-3,5-dione. The general approach involved introduction of the α- and ω-side-chain as entire units by step-wise N-alkylation. The problems encountered with this approach of competing N-and O-mono-and di-alkylation were overcome, eventually, such that judicious choice of the initial mono-N-alkylation step enabled the synthesis of analogues incorporating wide variations in the α- and ω-side-chain. Important structural modifications included introduction of unsaturation into the α-side-chain at the 5,6- position and of methyl groups into the ω-side-chain at the 15- and 16-position as exemplified by the synthesis of 1-[(Z)-6-carboxyhex-2-enyl]-2-(3-hydroxy-3,4-dimethyloctyl)-4-methyl-1,2,4-tri-azolidine-3,5-dione (19). The stable triazaprostaglandin analogues were synthesized as racemic compounds but, nevertheless, compound (19) possessed bronchodilator activity of a similar order to that of the natural prostaglandins PGE1 and PGE2.

Conformational analysis of the novel antihypertensive agent cromakalim (BRL34915)

N.m.r. analysis of the novel antihypertensive agent cromakalim shows that it adopts a rigid conformation in solution, similar to that observed in the crystalline state by an X-ray crystal structure determination.

1,2,5,6-tetrahydropyridine oxime ethers incorporating electron withdrawing groups are potent and selective muscarinic agonists

Abstract The combination of N-methoxy imidoyl halide and nitrile moieties with the 1,2,5,6-tetrahydropyridine ring system afforded a novel series of potent muscarinic agonists. Members of this class, exemplified by the imidoyl nitriles 2c and 3c , show favourable central selectivity. The incorporation of fluoroacetyl oxime ethers gave compounds with weak affinity for muscarmic receptors.

Bridged 1,2,5,6-tetrahydropyridine esters and oxime ethers related to arecoline are novel and potent muscarinic agonists

Abstract Constraining the 1,2,5,6-tetrahydropyridine ring of arecoline 1a and the related muscarinic agonists 1b–e by replacing the N-methyl group by an ethano bridge between the nitrogen and the C5-position afforded compounds 2a–e . These compounds have enhanced affinities for muscarinic receptors which supports our proposed binding conformation ( 1a ) ax of arecoline.

8,10,12-triazaprostaglandin analogues

Abstract A versatile synthetic procedure for the preparation of 8,10,12-triazaprostaglandin analogues is described.